Certain pyridinamines have pesticidal activities for combating noxious living beings such as insects, mites, fungi, bacteria and rodents. For example, compounds having rodenticidal activity are disclosed in U.S. Pat. No. 4,140,778 and compounds having pesticidal activity are disclosed in U.S. Pat. No. 3,965,109 and U.S. Pat. No. 3,926,611.
U.S. Pat. No. 4,331,670 discloses and claims N-pyridinamines having specific substituents on the pyridyl ring. These compounds are effective at combating noxious insects, mites, fungi, and bacteria on industrial products, seeds and fruits in storage, and for controlling noxious organisms growing on agricultural and horticultural crops and up-land. One of these compounds, fluazinam, is currently marketed for managing sclerotinia drop which is a major disease of lettuce caused by two soil borne fungi: S. minor and S. sclerotiorum. Fluazinam and other fungicides such as boscalid, fenhexamid, and fludioxonil have also demonstrated efficacy against diseases caused by S. minor and S. sclerotiorum on crops other than lettuce.
3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α,α,α-trifluoro-2,6-dinitro-p-toluidine (fluazinam) is also known to assist in the protection of container-grown aucuba from southern blight, a damaging hot weather disease afflicting a wide variety of flowering trees, shrubs and herbaceous ornamentals in both the nursery and landscape.
Fluazinam has a broad antifungal spectrum and shows good preventive effect against plant diseases. Fluazinam showed good activity against benzimidazole and/or dicarboximide resistant strains of B. cinerea. Field tests demonstrated excellent activity of fluazinam against potato Phycophthora infestans. Fluazinam was also shown to significantly reduce the population of mites by repeated treatments in the field. (ACS Symposium Series 1995 584, 443-8).
U.S. Pat. No. 4,331,670, the contents of which are incorporated by reference herein in their entirety, discloses a coupling process for the preparation of pyridinamines such as fluazinam according to the following scheme:

The reaction utilizes either THF or DMF as solvent, leading to a reported yield of 75% and 22%, respectively. The aforementioned solvents cause the reaction to suffer from many drawbacks. For example, THF is a flammable unsafe solvent with a low flash point and is a source for peroxide formation; hence its use in large-scale production is very limited. In addition, aprotic polar solvents such as THF and DMF are water-miscible and recycle as azeotropes containing high amounts of water. The presence of water lowers the yield of the reaction due to incomplete consumption of the reagents on one hand and the manufacture of hydrolysis byproducts on the other. For example, a competing side-reaction is the hydrolysis of compound (1A) in the presence of water to generate the resulting by-product of formula (4). This reaction significantly lowers the yield of the final product.

In addition, the prior art method involves very tedious work-up steps that involve extraction into a third solvent—ethyl acetate and purification on silica gel, which is unsuitable for large-scale manufacture. These complicated purification procedures are needed in order to remove the large amounts of impurities formed during the reaction such as the hydrolysis products described above, as well as accelerated tar formation at temperatures above 40° C., and incomplete consumption of both reagent 1A and 2A (mainly due to the dilute conditions under which the reaction is conducted—less then 8.2% w/v reagents to solvent).
To date, there are no simple methods for purifying fluazinam, which can be used on a large scale to produce highly pure product. There are also no known crystalline polymorphic forms of fluazinam. There is thus an urgent and unmet need in the art for efficient methods for the preparation and purification of fluazinam and other pyridinamines, which overcome the drawbacks and deficiencies of the prior art methods.